KR20010014294A - (S) 2-Methylamino-2-phenyl-n-butyl 3,4,5-trimethoxybenzoate, its application to the treatment of chronic pain - Google Patents
(S) 2-Methylamino-2-phenyl-n-butyl 3,4,5-trimethoxybenzoate, its application to the treatment of chronic pain Download PDFInfo
- Publication number
- KR20010014294A KR20010014294A KR1019997012424A KR19997012424A KR20010014294A KR 20010014294 A KR20010014294 A KR 20010014294A KR 1019997012424 A KR1019997012424 A KR 1019997012424A KR 19997012424 A KR19997012424 A KR 19997012424A KR 20010014294 A KR20010014294 A KR 20010014294A
- Authority
- KR
- South Korea
- Prior art keywords
- phenyl
- methylamino
- trimethoxybenzoate
- butyl
- acid
- Prior art date
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- 208000002193 Pain Diseases 0.000 title claims abstract description 38
- 208000000094 Chronic Pain Diseases 0.000 title claims abstract description 18
- ZFPDLGDYDUPYEZ-OAQYLSRUSA-N [(2s)-2-(methylamino)-2-phenylbutyl] 3,4,5-trimethoxybenzoate Chemical compound C([C@@](CC)(NC)C=1C=CC=CC=1)OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 ZFPDLGDYDUPYEZ-OAQYLSRUSA-N 0.000 title claims abstract description 15
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- ZFPDLGDYDUPYEZ-UHFFFAOYSA-N [2-(methylamino)-2-phenylbutyl] 3,4,5-trimethoxybenzoate Chemical compound C=1C=CC=CC=1C(CC)(NC)COC(=O)C1=CC(OC)=C(OC)C(OC)=C1 ZFPDLGDYDUPYEZ-UHFFFAOYSA-N 0.000 claims description 23
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C219/02—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C219/04—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C219/14—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the hydroxy groups esterified by a carboxylic acid having the esterifying carboxyl group bound to a carbon atom of a six-membered aromatic ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pain & Pain Management (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
본 발명은 만성 통증을 치료하기 위한 용도로서 화학식 (I)의 광학적으로 순수한 (S) 2-메틸아미노-2-페닐-n-부틸 3,4,5-트리메톡시벤조에이트를 제공한다. 본 발명은 또한 화학식 (I)의 화합물의 사용 방법 및 화학식 (I)의 화합물을 포함하는 약제학적 조성물을 제공한다.The present invention provides optically pure (S) 2-methylamino-2-phenyl-n-butyl 3,4,5-trimethoxybenzoate of formula (I) as a use for treating chronic pain. The invention also provides methods of using the compounds of formula (I) and pharmaceutical compositions comprising the compounds of formula (I).
Description
통증은 실제 또는 잠재적인 조직 손상 및 그것이 생성하는 감정의 수용을 반영하는 감각을 포함하는 복합적이고 주관적인 현상이다. 우선, 통증은 그의 세기 및 지속기간에 따라서 급성 또는 만성으로 기술된다. 따라서, 6개월을 초과하여 지속되는 통증은 만성 통증으로 기술된다. 이러한 첫번째 상이점에 추가하여, 통증은 다수의 방법으로 분류되고, 이에 대한 요약을 문헌[Merck Manual, Frnech ed. 1988 - Merck and Co., INC.]의 1422 페이지 이후에서 발견할 수 있다. 특히 주요한 문제점은 만성 통증의 치료에 관한 것이다. 통상적으로, 통증은 환자의 의식 상태 및 민감한 지각을 유지시키며 통증을 제거하는, 소위 진통제 활성을 갖는 화합물로 치료된다. 본질적으로, 이러한 화합물들은 비스테로이드성의 항염증 등급(NSAID) 또는 마취성 진통제에 속하고, 통증을 느끼는 정도 및 예상되는 치료 기간에 따라서 선택되어 환자에게 투여된다. 이러한 화합물들이, 특히 빈번한 치료학적 검사가 요구되고, 종종 환자에게 과도한 압박을 주는 만성 통증에 정확하게 필요한 장기 치료중에 요구되지않는 부작용을 야기하는 것으로 공지되어 있다. 따라서, 아라키돈 다단에서 프로스태글란딘 및 동통발생 트롬복산의 합성을 시클로옥시게나제의 억제에 의해 감소시키는 NSAID는 심각한, 특히 위장관 및 혈액에 부작용을 야기할 수 있는 것으로 공지되어 있다[The Pharmacological Basis of Therapeutics - Goodman & Gilman - 9th ed. p. 617-655 참조]. 또한, 마취성 진통제는 주요 효과(호흡기 억압, 메스꺼움 및 구토) 또는 주위 효과(위장관 운송) 이외에 약물 의존 현상을 야기하는 것으로 공지되어 있다[ibid. p. 521-555 및 p. 557-577 참조].Pain is a complex and subjective phenomenon that involves real or potential tissue damage and sensations that reflect the acceptance of the emotions it produces. First of all, pain is described as acute or chronic, depending on its intensity and duration. Thus, pain lasting longer than six months is described as chronic pain. In addition to this first difference, pain is classified in a number of ways, a summary of which is described in Merck Manual, Frnech ed. 1988-Merck and Co., INC., After page 1422. In particular the main problem relates to the treatment of chronic pain. Typically, pain is treated with a compound having so-called analgesic activity that maintains the patient's state of consciousness and sensitive perception and eliminates pain. In essence, these compounds belong to a nonsteroidal anti-inflammatory grade (NSAID) or anesthetic analgesic and are selected and administered to the patient depending on the extent of pain and the expected duration of treatment. Such compounds are known to cause undesired side effects during long-term treatment, particularly where frequent therapeutic tests are required and are often precisely needed for chronic pain that exerts excessive pressure on the patient. Thus, NSAIDs that reduce the synthesis of prostaglandins and pain-producing thromboxanes in arachidone cascades by inhibition of cyclooxygenase are known to cause serious, especially gastrointestinal and blood side effects. The Pharmacological Basis of Therapeutics-Goodman & Gilman-9th ed. p. 617-655]. In addition, narcotic analgesics are known to cause drug dependence in addition to the main effects (respiratory depression, nausea and vomiting) or ambient effects (gastrointestinal transport) [ibid. p. 521-555 and p. 557-577].
지금까지, 세계 보건 기구에 따르면 적절한 치료의 부족으로 인해 전세계적으로, 예를 들면 4백만명의 암 환자들을 포함하여 다수의 사람들에게 다양한 형태로 영향을 미치는 만성 통증의 치료에 대한 해결책이 매우 불만족스럽다는 것이 주요한 문제점으로 존재하고 있다. 암에 추가하여, 통증 또는 신체적 및 정신적 구성요소에 관한 만성 통증 증후군의 영역에 있어서, 근골격 또는 척추 통증, 신경학상 통증, 두통 또는 혈관 통증과 같은 다수의 상태가 존재한다.To date, according to the World Health Organization, the lack of adequate treatment has resulted in very unsatisfactory solutions to the treatment of chronic pain that affects a large number of people worldwide, including, for example, 4 million cancer patients. Is a major problem. In addition to cancer, in the area of pain or chronic pain syndrome with regard to physical and mental components, there are a number of conditions such as musculoskeletal or spinal pain, neurological pain, headache or vascular pain.
본 발명의 생성물과 관련된 선행 기술의 화합물 측면에서, 1976년 5월 5일 발간된 GB 1,434,826는 라세미 아미노 알콜의 에스테르 및 카르바메이트 및 그들 중에서 화학식 (II)의 에스테르류를 특허청구하고 있다.In terms of prior art compounds relating to the products of the present invention, GB 1,434,826, published May 5, 1976, claims esters and carbamates of racemic amino alcohols and among them esters of formula (II).
(상기식에서, 보다 구체적으로는(In the above formula, more specifically
R'1, R'2, R'3는 수소이고,R ' 1 , R' 2 , R ' 3 are hydrogen,
R'4는 C1-C4알킬이고,R ' 4 is C 1 -C 4 alkyl,
R'5및 R'6는 유사하거나 상이한 수소 또는 C1-C4알킬이고,R ' 5 and R' 6 are similar or different hydrogen or C 1 -C 4 alkyl,
R'7은 C1-C4알콕시 라디칼로 이루어진 집합에서 선택되는 1 내지 3개의 기로 임의로 치환된 아릴임)R ' 7 is aryl optionally substituted with one to three groups selected from the group consisting of C 1 -C 4 alkoxy radicals)
이러한 에스테르는 운동성 및 위장관 운송-억제 특성 및 국부 마취 특성에 추가하여, 소화기 질환에 있어서 통증의 치료에 유용한 진통성 및 항염증성 화합물을 포함하는 것으로 알려져 있다. 또한, 1980년 5월 1일 발간된 일본 특허 제16416/1980호에서는 그의 라세메이트가 진경성 활성을 갖는 트리메부틴(INN)인 2-디메틸아미노-2-페닐-n-부틸 3,4,5-트리메톡시벤조에이트를 기술 및 특허청구하고 있다[FR 2,369M - 1962 참조]. 또한 일본 특허 공보는 화합물의 임의의 활성을 언급하지 않고 특허청구된 방법에 의해 (+) 및 (-) 에난티오머의 합성을 예시하고 있다.Such esters are known to include analgesic and anti-inflammatory compounds useful in the treatment of pain in gastrointestinal disorders, in addition to motility and gastrointestinal transport-inhibitory properties and local anesthetic properties. In addition, Japanese Patent No. 16616/1980, published May 1, 1980, discloses that the racemate is 2-dimethylamino-2-phenyl-n-butyl 3,4, which is trimebutin (INN) having an allergic activity. 5-trimethoxybenzoate has been described and claimed (see FR 2,369M-1962). The Japanese Patent Publication also exemplifies the synthesis of (+) and (-) enantiomers by the claimed method without mentioning any activity of the compounds.
말레산 트리메부틴의 대사 연구는 다른 대사물질에 추가하여 (R,S) 2-메틸아미노-2-페닐-n-부틸 3,4,5-트리메톡시벤조에이트를 확인하게 한다[마가리부치(Magaribuchi T.) 등의 Oyo Yakuri (1982), 24 (5), 625-9) 참조]. 정맥으로 투여되는 이러한 화합물은 쥐에 있어서 위의 운동성을 억제하고 혈압을 완화하고 심박수를 감소시킨다.Metabolic studies of maleic acid trim mebutin have allowed us to identify (R, S) 2-methylamino-2-phenyl-n-butyl 3,4,5-trimethoxybenzoate in addition to other metabolites [Margaribuchi (Ogaro Yakuri (1982), 24 (5), 625-9) of Magaribuchi T. et al.]. Intravenously, these compounds inhibit gastric motility, relieve blood pressure and reduce heart rate in rats.
이러한 NDTMB(N-데메틸트리메부틴)이라 불리는 라세미 대사물질의 추가 연구는 하기 사항을 입증한다.Further studies of such racemic metabolites called NDTMB (N-demethyltrimebutin) demonstrate the following.
-시험관내, κ 및 δ형 마취성 수용체에 대한 친화도보다 적당하고, 말초 마취성 수용체를 통한 위장관 운동성에 관해 연구된 생성물의 활성을 확인시키는 μ형 마취성 수용체에 대한 작용제 친화도를 설명한다[로만(Roman F.) 등의 J. Pharm. Pharmacol. (1987), 39(5), 404-7 참조]. 아유형에 대한 임의의 현저한 특이성이 없이, 이러한 마취성 친화도가 확인되어 있다[파스코드(Pascaud, X.) 등의 Gastroenterol. Clin. Biol. (1987), 11 (3), 77B-81B 참조]In vitro, describes affinity of agonists to μ-type anesthetic receptors that are more appropriate than affinity to κ and δ anesthetic receptors and confirm the activity of the studied product with respect to gastrointestinal motility through peripheral anesthetic receptors. [Roman F. et al. J. Pharm. Pharmacol. (1987), 39 (5), 404-7]. Without any significant specificity for subtypes, such anesthetic affinity has been identified (Pascaud, X. et al. Gastroenterol. Clin. Biol. (1987), 11 (3), 77B-81B].
-생체내, 개에게 경구 또는 정맥내로 투여된 NDTMB가 위장관 및 결장의 운동성에 대한 트리메부틴의 효과에 참여하는 것이 확증되어 있다[부에노(Bueno, L.) 등의 Gastroenterol. Clin. Biol. (1987), 11 (3), 90B-93B 참조]. 개에게 경구 투여함으로써, NDTMB는 κ 길항제에 의해서 억제되는 효과인 공복을 촉진시키고, 이는 안트로듀오데날(antroduodenal) 수준에서 점막 또는 점막하의 κ 수용체의 국부 자극에 의한 생성물의 효과를 제시한다[구에(Gue, M.) 등의 J. Pharm. Pharmacol. (1988), 40 (12), 873-5 참조].NDTMB administered in vivo, orally or intravenously to dogs has been shown to participate in the effects of trimebutin on motility of the gastrointestinal tract and colon [Bueno, L. et al. Gastroenterol. Clin. Biol. (1987), 11 (3), 90B-93B]. By oral administration to dogs, NDTMB promotes fasting, an effect inhibited by κ antagonists, suggesting the effect of the product by local stimulation of the mucosal or submucosal κ receptor at the anthrodudenal level. J. Pharm. Et al. (Gue, M.). Pharmacol. (1988), 40 (12), 873-5].
보고된 바와 같이, 본 발명의 주제와 가장 근접하게 관련된 선행 기술은 트리메부틴의 공지된 대사물질인 (R,S) 2-메틸아미노-2-페닐-n-부틸 3,4,5-트리메톡시벤조에이트이다. 지금까지, 이러한 대사물질에 대하여 수행되어온 연구는 트리메부틴의 전체적 효과에 참여하는 것으로 생각되고, 장의 운동성을 자극하고 자극후 그것을 억제가능하게 하는 말초 엔케팔리너직 길항 활성에 관련된, 소화 운동성을 개질하는 근친화성 진경제 화합물인 것으로 보고되는 대사물질이 되는 그의 전구체의 그것에 유사한 활성을 입증한다. 따라서, 본 발명의 주제인 (S) 에난티오머의 모화합물인 라세메이트는 트리메부틴과 같이 위장관 및 담즙 도관의 기능성 질환의 치료 및 결과적으로 이러한 질환으로부터 야기되는 통증의 징후의 환자를 구제하는데 잠재적으로 유용하다.As reported, the prior art most closely related to the subject matter of the present invention is (R, S) 2-methylamino-2-phenyl-n-butyl 3,4,5-tri, a known metabolite of trimebutin. Methoxybenzoate. So far, studies that have been conducted on these metabolites are thought to participate in the overall effects of trimebutin and modify digestive motility, which is related to peripheral enkephalinergic antagonistic activity that stimulates intestinal motility and makes it possible to inhibit it after stimulation. Demonstrates similar activity to that of its precursor, which is a metabolite reported to be an affinity antispasmodic compound. Accordingly, racemate, the parent compound of the subject (S) enantiomer of the present invention, is used to treat patients with functional diseases of the gastrointestinal tract and bile ducts, such as trimebutin, and consequently for the manifestation of signs of pain resulting from these diseases. Potentially useful
마취성 수용체에 대한 친화도를 갖는 화합물의 연구에 관해서, 화합물이 비대칭적인 탄소 원자를 가질때, 그로 인해 정반대의 절대 배열 (R 또는 S)를 갖고 그들의 동일량의 혼합물이 (R,S) 라세메이트라고 불리는 2종의 에난티오머를 생성하며, 친화도는 입체특이성, 즉 에난티오머중 하나에 선택적인 것으로 공지되어 있다. 관례에 따라, 수용체에 대해 가장 높은 친화도를 갖는 에난티오머를 유토머라고 하고, 보다 덜 활성 또는 심지어 비활성인 에난티오머를 디스토머라고 한다.Regarding the study of compounds having an affinity for anesthetic receptors, when the compounds have asymmetric carbon atoms, they have the opposite absolute arrangement (R or S) and their equivalent mixtures of (R, S) racemates It produces two kinds of enantiomers called and its affinity is known to be selective for stereospecificity, ie enantiomers. By convention, enantiomers with the highest affinity for the receptor are called utomers, and less active or even inactive enantiomers are called dystomers.
트리메부틴 및 그의 대사물질 NDTMB는 동일한 비대칭성 탄소 원자를 포함하고 라세미 혼합물이다. 잠재적으로, 마취성 수용체와 관련하여 그들 모두는 배열의 역전을 허용하지 않는 비대칭성 탄소 원자의 치환체의 특성으로 주어지고, 또한 N-탈메틸화가 칸 인골드 및 프리로그(Cahn Ingold and Prelog) 규칙에 따라서 결정된 이러한 배열을 개질하지 못한다는 사실로 인해 동일한 절대 배열을 갖는 유토머 형태이다. 그러나, 트리메부틴의 에난티오머가 특허 JP 16416/1980에서 언급된 바와 같이 제조되는 반면, 그들의 대사물질인 NDTMB는 신규한 것들이다. 라세메이트 및 이러한 생성물에 대한 유토머 형태의 가능성의 유리한 특징으로 주어지기 때문에, 본 출원인들은 이러한 화합물, 에난티오머 및 라세메이트의 시험관내 및 생체내 연구를 수행해왔다.Trimebuterin and its metabolite NDTMB contain the same asymmetric carbon atoms and are racemic mixtures. Potentially, with regard to anesthetic receptors, all of them are given the properties of substituents of asymmetric carbon atoms that do not allow reversal of the arrangement, and also N-demethylation is subject to the Cahn Ingold and Prelog rules. Therefore, due to the fact that this arrangement cannot be modified, it is a utomer form with the same absolute arrangement. However, while enantiomers of trimebutin are prepared as mentioned in patent JP 16416/1980, their metabolite NDTMB is novel. Given the advantageous features of the potential of the racemates and the eutomer form for these products, we have conducted in vitro and in vivo studies of such compounds, enantiomers and racemates.
본 명세서에 보고된 연구는 마취성 수용체에 대한 그의 친화도의 견지에서 디스토머로서 입증된 대사물질 NDTMB의 (S) 배열의 에난티오머가 생체내에서 만성 통증의 치료에 사용하기에 특히 유리한 진통제 특성을 나타낸다는 것을 매우 놀랍게도 나타내 왔다. 실제로, 그의 (R) 대장체와 비교하여 마취성 수용체에 대해 친화도가 낮음에도 불구하고, 이러한 에난티오머는 동물에 있어서 만성 통증의 대표적인 약물학적 모델에서 강력한 진통 효과 및 마취 부작용이 없는 것으로 증명되고 있다.The studies reported herein indicate that analgesic properties of the (S) configuration of the metabolite NDTMB, which has been demonstrated as a destomer in terms of its affinity for anesthetic receptors, are particularly advantageous for use in the treatment of chronic pain in vivo. It has been surprisingly shown. Indeed, despite its low affinity for anesthetic receptors compared to its (R) colon, these enantiomers have proven to be free of potent analgesic effects and anesthetic side effects in representative pharmacological models of chronic pain in animals. have.
<발명의 요약>Summary of the Invention
본 발명은 광학적으로 순수한 (S) 2-메틸아미노-2-페닐-n-부틸 3,4,5-트리메톡시벤조에이트, 그의 약제학적으로 허용가능한 산과의 부가염 및 그들의 제조 방법에 관한 것이다.The present invention relates to optically pure (S) 2-methylamino-2-phenyl-n-butyl 3,4,5-trimethoxybenzoate, addition salts with pharmaceutically acceptable acids thereof and methods for their preparation. .
또다른 측면에서, 본 발명은 다양한 병인의 만성 통증의 치료에 있어서 이러한 화합물을 포함하는 의약 조성물, 그들의 제법 및 그들의 치료학적 사용에 관한 것이다.In another aspect, the present invention relates to pharmaceutical compositions comprising these compounds, their preparation and their therapeutic use in the treatment of chronic pain of various etiologies.
본 발명의 주제는 광학적으로 순수한 화학식 (I)의 (S) 2-메틸아미노-2-페닐-n-부틸 3,4,5-트리메톡시벤조에이트 및 그의 약제학적으로 허용가능한 부가염, 그들의 제법 및 다양한 병인의 만성 통증을 치료하기 위한 약제 형태로서의 치료학적 용도이다.Subject of the invention are optically pure (S) 2-methylamino-2-phenyl-n-butyl 3,4,5-trimethoxybenzoate of formula (I) and pharmaceutically acceptable addition salts thereof, their It is a therapeutic use as a pharmaceutical form for the preparation and treatment of chronic pain of various etiologies.
첫번째 측면에서, 본 발명은 광학적으로 순수한 (S) 2-메틸아미노-2-페닐-n-부틸 3,4,5-트리메톡시벤조에이트 및 약제학적으로 허용가능한 산과의 부가염에 관한 것이다.In a first aspect, the present invention relates to addition salts with optically pure (S) 2-methylamino-2-phenyl-n-butyl 3,4,5-trimethoxybenzoate and pharmaceutically acceptable acids.
광학적으로 순수하다는 것은, 약제학적 공업 규격에 따라서 설정된 화학적 순도에 추가하여, 화합물이 실질적으로 그의 (R) 대장체로부터 정제된 것이며, 이는 최소한의 광학적 순도에 대하여 본 발명에 따른 생성물이 90 중량% 이상의 (S) 에난티오머를 함유하거나, 상이하게 표현하면 요구되지 않는 (R) 에난티오머를 10 중량% 미만으로 포함하는 것을 의미한다. 어떠한 경우에서도, 바람직한 광학 순도는 99 중량% 이상의 (S) 에난티오머, 또는 많아야 1 중량%의 광학적 불순물인 (R) 에난티오머를 포함하는 본 발명에 따른 화합물의 것과 상응하고, 이러한 수준은 적절한 분석 방법에 의해 측정된다.Optically pure is, in addition to the chemical purity set according to the pharmaceutical industry standard, that the compound is substantially purified from its (R) colon, which is 90% by weight of the product according to the invention for minimal optical purity. Containing the above-mentioned (S) enantiomer or expressing differently, it means containing less than 10 weight% of (R) enantiomer which is not required. In any case, the preferred optical purity corresponds to that of the compound according to the invention comprising at least 99% by weight of (S) enantiomer, or at most 1% by weight of optical impurity (R) enantiomer, which level is It is measured by an appropriate analytical method.
약제학적으로 허용가능한 산과의 부가염에서, 이러한 산들의 광범위한 목록을 문헌[J. Pharm. Sci., 1977, 66, 1-19]에서 찾을 수 있다. 이러한 무기 또는 유기산은, 예를 들면 브롬화 수소산, 염산, 황산, 인산, 질산, 아세트산, 석신산, 타르타르산, 시트르산, 말레산, 히드록시말레산, 벤조산, 푸마르산, 톨루엔술폰산 및 이세티온산등과 같이 비독성인 것으로 알려져 있다. 그러나, 염산, 말레산 및 타르타르산이 바람직하고, 특히 타르타르산의 중성 L(+) 이성체가 바람직하다.In addition salts with pharmaceutically acceptable acids, an extensive list of such acids is given in J. Pharm. Sci., 1977, 66, 1-19. Such inorganic or organic acids are, for example, hydrobromic acid, hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, succinic acid, tartaric acid, citric acid, maleic acid, hydroxymaleic acid, benzoic acid, fumaric acid, toluenesulfonic acid and isethionic acid. It is known to be nontoxic. However, hydrochloric acid, maleic acid and tartaric acid are preferred, and neutral L (+) isomers of tartaric acid are particularly preferred.
또한, 본 발명은 본 발명의 화합물 및 그의 염의 제조 방법에 관한 것이다. (S) 2-메틸아미노-2-페닐-n-부틸 3,4,5-트리메톡시벤조에이트의 제조 방법은 라세미 혼합물을 제조한후 그것을 분리하거나, 바람직한 방법에 따라서 (S) 배열의 에난티오머 전구체로부터 화학적 합성을 수행하는 것으로 이루어져 있다.The invention also relates to a process for the preparation of the compounds of the invention and salts thereof. (S) A method for preparing 2-methylamino-2-phenyl-n-butyl 3,4,5-trimethoxybenzoate is prepared by preparing a racemic mixture and then separating it, or according to a preferred method, Consisting of performing chemical synthesis from enantiomer precursors.
라세미 화합물의 분리에 관한 방법은, 분리되며 적절한 처리에 의해 (S) 배열의 에난티오머인, 본 발명의 목적 및 그에 따르는 또한 그의 디스토머 (R) 대장체의 연구를 위한 유토머를 생성하는 2종류의 디아스테레오이성체 부가염으로 처리된 라세미 화합물을 얻기위해서 광학적으로 활성인 산을 사용하는 것으로 이루어져 있다. 또한, 키랄 칼럼상에서 액체 크로마토그래피에 의해 라세미 화합물을 직접 분리하는 방법을 사용할 수 있다.The method for the isolation of racemic compounds produces a utomer for the purpose of the present invention, which is also an enantiomer of the (S) configuration, and accordingly also for the study of its distorant (R) colon, by separation and appropriate treatment. It consists of using an optically active acid to obtain a racemic compound treated with two kinds of diastereoisomeric addition salts. It is also possible to use a method of directly separating racemic compounds by liquid chromatography on chiral columns.
그러나, (S) 2-메틸아미노-2-페닐-n-부틸 3,4,5-트리메톡시벤조에이트의 바람직한 제조 방법은 반응식 1에 나타낸 바와 같이 본질적으로However, the preferred process for preparing (S) 2-methylamino-2-phenyl-n-butyl 3,4,5-trimethoxybenzoate is essentially as shown in Scheme 1.
- 붕소 또는 알루미늄으로부터 유도된 수소화물 복합체를 사용하여 (S) 2-포르밀아미노-2-페닐-n-부티르산 (III)을 환원시켜 (S) 2-메틸아미노-2-페닐-n-부탄올 (II)를 얻는 단계,Reduction of (S) 2-formylamino-2-phenyl-n-butyric acid (III) using a hydride complex derived from boron or aluminum to (S) 2-methylamino-2-phenyl-n-butanol Obtaining (II),
- 아미노 알콜 (II)을 공정 A의 3,4,5-트리메톡시벤조일 클로라이드 및 공정 B의 메틸 3,4,5-트리메톡시벤조에이트로 에스테르화하여 (S) 2-메틸아미노-2-페닐-n-부틸 3,4,5-트리메톡시벤조에이트 (I)을 얻는 단계Amino alcohol (II) is esterified with 3,4,5-trimethoxybenzoyl chloride of step A and methyl 3,4,5-trimethoxybenzoate of step B to give (S) 2-methylamino-2 Obtaining -phenyl-n-butyl 3,4,5-trimethoxybenzoate (I)
로 이루어진다.Is made of.
본 발명의 주제는 또한 약제로서 본 발명의 화합물 (I) 및 그의 염의 용도 뿐만 아니라 이러한 생성물이 활성 성분로서 사용되고, 만성 통증의 치료에 유용한 의약 형태의 제제를 목적으로 하는 조성물이다.The subject of the present invention is also a composition aimed at the use of the compound (I) and salts thereof of the present invention as a medicament, as well as preparations in medicinal form where such products are used as active ingredients and are useful in the treatment of chronic pain.
앞서 언급한 바와 같이, 본 출원인들은 라세메이트인 (S) 에난티오머 및 전구체, 즉 트리메부틴 TMB와 비교하여 대사물질 NDTMB의 (R) 및 (S) 에난티오머의 마취성 수용체에 대한 친화도의 입체특이성을 측정하기 위한 연구를 수행해왔다. 이러한 시험관내 연구는 이러한 시험에서 다양한 μ, δ 및 κ 아유형에 대한 0.3 내지 0.4의 대장체에 대하여 유디즘 비율(eudismic ratio)을 갖는 (R) 배열의 유토머에 대한 선택적 친화도를 나타내거나, 달리 표현하면 (R) 유토머의 친화도가 이러한 수용체의 (S) 대장체보다 2.5 내지 3배정도 크다는 것을 나타낸다. 또한, TMB 및 NDTMB 라세메이트의 개별 친화도는 매우 상이하지는 않지만, NDTMB의 친화도는 δ 및 κ 아유형보다 낮다.As mentioned earlier, the Applicants affinity for the anesthetic receptor of the (R) and (S) enantiomers of the metabolite NDTMB as compared to the racemate (S) enantiomer and precursor, ie trimebutin TMB. Research has been conducted to determine the stereospecificity of the figure. Such in vitro studies show selective affinity for the utomers of the (R) configuration with a eudismic ratio for the colon from 0.3 to 0.4 for the various μ, δ, and κ subtypes in this test. In other words, the affinity of the (R) utomer is 2.5 to 3 times greater than the (S) colon of these receptors. In addition, although the individual affinity of TMB and NDTMB racemates is not very different, the affinity of NDTMB is lower than the δ and κ subtypes.
생체내 연구를 계속하며, 본 출원인들은Continuing in vivo research, the applicants
- 마우스의 다리에 포름알데히드 용액을 주입하여 야기시키는 (지발성) 강직성 통증에 대한 진통 활성,Analgesic activity against (latency) ankylosing pain caused by injecting formaldehyde solution into the legs of the mouse,
- 쥐에서 PGE2에 의해 유도되는 만성 통각과민에 대한 진통 활성Analgesic activity against chronic hyperalgesia induced by PGE2 in rats
과 같은 만성 통증을 대표하는 것으로 인식되는 시험에 있어서 NDTMB, (R) 및 (S) 에난티오머를 사용했다.NDTMB, (R) and (S) enantiomers were used in tests recognized as representative of chronic pain.
시험의 결과는 놀랍게도 마취성 수용체에 보다 낮은 친화도를 가지는 (S) 에난티오머가 시험에 따라서 단지 매우 부분적으로 마취 성질을 갖기 때문에, 그 활성이 특히 유리한 것으로 고려되어야만 될 라세미 NDTMB 및 그의 (R) 대장체와 동일하거나 초과하는 진통 활성을 갖는다. 실제로, 다른 2종의 성분과 대조하여, (S) 에난티오머의 진통 효과는 단지 날옥손에 의해 부분적으로 억제되고, 이는 소위 마취성 진통제, 특히 μ친화도를 갖는 것들의 길항제로서 공지되어 있다. 또한, 좌골 신경의 결찰에 의해 야기되는 신경장애 통증 또는 쥐에 있어서 스트렙토조신에 의해 유도되는 실험 당뇨에 의해 야기되는 통증과 같은 특정 만성 통증의 대표적인 모델에 대한 생성물의 연구 및 쥐에서 카라제닌에 의해 야기되는 염증성 통증에 대한 행동학적 연구는 이러한 장점을 확인시킨다. 최종적으로, (S) 에난티오머는 그의 (R) 대장체와는 다르게 마취성 약물의 반복 투여후 의존증을 나타내는 것으로 알려진 시험에 사용될때 어떠한 몰핀 형태의 금단 효과도 나타내지 않는다.The results of the test surprisingly indicated that racemic NDTMB and its (R), whose activity is to be considered particularly advantageous, since (S) enantiomers with lower affinity for anesthetic receptors have only very partial anesthetic properties depending on the test. ) Has the same or more analgesic activity as the colon. In fact, in contrast to the other two components, the analgesic effect of (S) enantiomer is only partially inhibited by naloxone, which is known as an antagonist of so-called anesthetic analgesics, in particular those having μ affinity. . In addition, studies of products for representative models of specific chronic pain, such as neuropathic pain caused by ligation of the sciatic nerve or pain caused by experimental diabetes induced by streptozosin in rats, and by carrageenin in rats Behavioral studies of the resulting inflammatory pain confirm this advantage. Finally, (S) enantiomers, unlike their (R) colon, do not exhibit any morphine-type withdrawal effect when used in tests known to show dependence after repeated administration of anesthetic drugs.
이러한 생체내 연구 및 진통 특성을 고려하면, 본 발명의 (S) 에난티오머는 상기 시험관내 수용체 연구와 대조하여, 예를 들면 골관절염, 다중관절염, 척추염, 수술후 통증, 외상, 통증성 대상포진 후유증, 다중신경장애, 사지 절단 및 동맥염 또는 정맥류성궤양과 같은 혈관 상태와 같은 만성 통증의 치료에 적용된다는 점에서 유토머이다.In view of these in vivo studies and analgesic properties, the (S) enantiomer of the present invention, in contrast to the in vitro receptor studies, for example osteoarthritis, polyarthritis, spondylitis, postoperative pain, trauma, painful shingles sequelae, It is a utomer in that it is applied to the treatment of chronic pain such as multiple neuropathy, limb amputation and vascular conditions such as arteritis or varicose ulcer.
본 발명의 화합물 및(또는) 그의 염중 하나는 치료되어질 상태의 성질 및 심각성에 대하여 채용된 의약 형태로 환자에게 투여된다. 사람의 일일 투여량은 대개 단일 또는 분할된 분량으로 복용할 수 있는 활성 성분의 2 내지 1.0 g이다. 당분야의 숙련자들에게 일반적인 기술에 따라 제조된 조성물은 0.5 내지 75 중량%의 활성 성분 및 화학적, 물리적으로 활성 성분와 상용가능한 99.5 내지 25 중량%의 적절한 부형제를 포함하며 예상하고 있는 투여 경로에 채용되는 의약 형태로 얻어진다. 비제한적인 실례로서, 정제, 당의정, 캡슐, 좌약, 국부 도포 또는 접종 보조를 위한 겔, 주사 또는 경구 투여를 위한 용액으로 제조된다.One of the compounds of the invention and / or salts thereof is administered to the patient in the form of a medicament employed for the nature and severity of the condition to be treated. The daily dosage of a human is usually from 2 to 1.0 g of the active ingredient, which can be taken in single or divided doses. Compositions prepared according to techniques common to those skilled in the art comprise from 0.5 to 75% by weight of the active ingredient and from 99.5 to 25% by weight of suitable excipients compatible with chemically and physically active ingredients and are employed in the anticipated route of administration. Obtained in medicinal form. As a non-limiting example, it is prepared in tablets, dragees, capsules, suppositories, gels for topical application or inoculation assistance, solutions for injection or oral administration.
보다 구체적으로, 본 발명의 화합물의 제조를 위한 방법이라는 점에서,More specifically, in that it is a method for preparing a compound of the present invention,
-라세메이트의 분리Separation of racemates
a) 디아스테레오이성체염을 통한 분리 방법이라는 점에서, 이 방법은 라세메이트를 적절한 용매에서 광학적으로 활성인 산과 반응시켜 용매중 용해도의 상이함에 의해 분리되는 두 디아스테레오이성체를 형성한다. 가장 낮은 용해도를 갖는 디아스테레오이성체가 침전되고, 여과에 의해 단리된다. 분리된 염은 선택적인 용매에서 재결정화되어 만족스러운 광학 순도로 얻어지거나, 기본 매질로 처리되어 개별적인 에난티오머로 재생될 수 있다. 이러한 것들은 재결정에 의해 정제되거나 신규 디아스테레오이성체를 형성함으로써 제2 정제 단계에 사용될 수 있으며, 임의로는 앞서의 것과는 상이한 광학적으로 활성인 산을 이용한다. 디아스테레오이성체염의 제조에 일반적으로 사용되는 산의 에난티오머는 비제한적인 실례로서 α-페닐글리신, α-페닐알라닌 및 그들의 N-카르복실화된 유도체, 말산, 만델산, 타르타르산의 염 및 그들의 산과의 에스테르화 유도체, 또는 캄판산, 3-브로모-8-캄포술폰산 및 그의 위치 이성체, α-메톡시-α-트리플루오로메틸페닐아세트산이다. 이러한 산들의 에난티오머는 시판중이며, 그들의 용도가 상세히 기술되어 왔다. 따라서, 그들은 라세메이트의 분리 또는 에난티오머중 1종이 풍부한 임의의 혼합물의 정제에 적절하다.a) In the separation method via diastereoisomeric salts, this method reacts the racemate with an optically active acid in a suitable solvent to form two diastereoisomers which are separated by different solubility in the solvent. Diastereoisomers with the lowest solubility are precipitated and isolated by filtration. The separated salt can be recrystallized in an optional solvent to obtain a satisfactory optical purity, or it can be treated with a base medium to be regenerated into individual enantiomers. These can be purified by recrystallization or used in the second purification step by forming new diastereoisomers, optionally using a different optically active acid than the foregoing. Acid enantiomers commonly used in the preparation of diastereoisomeric salts include, by way of non-limiting example, α-phenylglycine, α-phenylalanine and their N-carboxylated derivatives, salts of malic acid, mandelic acid, tartaric acid and their acids. Esterified derivatives, or camphoric acid, 3-bromo-8-camphorsulfonic acid and positional isomers thereof, α-methoxy-α-trifluoromethylphenylacetic acid. Enantiomers of these acids are commercially available and their use has been described in detail. Thus, they are suitable for the separation of racemates or the purification of any mixture rich in one of the enantiomers.
디아스테레오이성체염의 제조는 1 mol의 라세메이트 또는 분리되거나 정제될 혼합물에 대해 물과 완전히 또는 부분적으로 혼화가능하고, 대개 알콜, 케톤, 저분자량 에테르 또는 아세토니트릴에서 선택되는 0.25 내지 2.00 mol의 용매 또는 용매의 혼합물중 에난티오머 용액을 반응시키는 것으로 이루어져 있다.The preparation of diastereoisomeric salts is completely or partially miscible with water for 1 mol of racemate or the mixture to be separated or purified, and usually 0.25 to 2.00 mol of solvent selected from alcohols, ketones, low molecular weight ethers or acetonitrile or It consists of reacting an enantiomeric solution in a mixture of solvents.
바람직하게는, 에탄올, 메탄올 또는 아세톤중 용액에서 1 mol의 처리될 생성물에 대해 0.5 내지 1.25 mol의 산 에난티오머를 반응시킴으로써 일반적으로 바람직한 20℃에서부터 사용된 용매의 비등점까지의 온도 범위에서 반응을 수행한다. 염생성은 5분 내지 3시간의 경과후에 완결된다. 이후 반응 혼합물을 방치하고, 우선 실온으로, 임의로는 0℃ 부근으로 하여 최소 가용성 디아스테레오이성체를 결정화하며, 이 결정화는 기대되는 염의 결정을 시드화함으로써 임의로 촉진된다. 결정화 종료시 또는 요구되는 광학 순도를 얻기에 적절한 것으로 평가된 시점에서, 결정화된 디아스테레오이성체를 여과하여 분리한다. 각각 보다 크거나 작은 정도로 정제된 디아스테레오이성체를 포함하는 두 상을 염에 대해서 정제하거나 그의 염으로부터 에난티오머를 방출하는 것에 대하여 개별적으로 처리하는데, 이는 수성 매질에서 알칼리성 처리에 의해 수행한후, 방출된 에난티오머를 여과 또는 추출한다.Preferably, the reaction is carried out in the temperature range from generally preferred 20 ° C. to the boiling point of the solvent used, by reacting 0.5 to 1.25 mol of acid enantiomer to 1 mol of the product to be treated in a solution in ethanol, methanol or acetone. Perform. Salt formation is complete after 5 minutes to 3 hours. The reaction mixture is then left to stand, first crystallizing the minimum soluble diastereoisomer to room temperature, optionally around 0 ° C., which crystallization is optionally promoted by seeding the crystals of the expected salt. At the end of crystallization or at a time point deemed appropriate to achieve the required optical purity, the crystallized diastereoisomers are separated by filtration. Two phases, each comprising diastereoisomers purified to a greater or lesser extent, are treated separately for purifying the salt or for releasing enantiomers from the salt, which is carried out by alkaline treatment in an aqueous medium, The released enantiomer is filtered or extracted.
b) 라세메이트의 분리 또는 칼럼 액체 크로마토그래피에 의한 임의의 에난티오머 혼합물의 정제에 관해서는, 다양한 키랄성 또는 비키랄성 지지체가 이러한 분리에 사용될 수 있다.b) As regards the separation of racemates or the purification of any enantiomer mixture by column liquid chromatography, various chiral or achiral supports can be used for this separation.
따라서, 적절한 방법이 JP 05215736 특허 공보에 기술되어 있는 것으로부터 채용되고, 고정상으로서 키랄셀(chiralcel) OJ(공급원 Diacel Chem.) 상과 같은 다당류의 카르복실산 에스테르를 사용하고, 완충 용액(예를 들면, HClO4- NaClO40.1 M)과 아세토니트릴과 같은 수혼화성 유기 용매의 혼합물을 사용하여 용출을 수행하는 것으로 이루어져 있다.Thus, a suitable method is employed from what is described in JP 05215736 Patent Publication, using a carboxylic acid ester of a polysaccharide such as a chiralcel OJ (source Diacel Chem.) Phase as a stationary phase, and using a buffer solution (e.g. For example, the elution is carried out using a mixture of HClO 4 -NaClO 4 0.1 M) and a water miscible organic solvent such as acetonitrile.
- (S)의 전구체로부터의 화학 합성에 의해서; (S) 에난티오머 및 2-포르밀아미노-2-페닐-n-부티르산의 (R,S) 라세미 혼합물이 공지되어 있고, 그들의 제법이 소보트카(sobotka)등의 문헌[J. of Am. Chem. Soc., 54, 1932, p. 4697]에 기술되어 있다. 이러한 화합물을 제조하기 위해, 방법이 수용한 장점은 프로피오페논을 시안산 칼륨 및 탄산 암모늄과 부쉬러-베르그(Busherer-Berg) 반응시켜 (+/-) 5-에틸-5-페닐히단토인을 얻으며, 이는 알칼리성 수성-아세톤 매질에서 (R)-α-메틸벤질아민으로 입체특이적 염화되어 히단토인의 (S) 에난티오머와의 부가염을 얻게 되는 것으로 이루어지고, 불용성 염은 산성 용액을 사용한 처리에 의해 여과 제거되고, 그로부터 (S) 5-에틸-5-페닐히단토인이 특허 EP 0,510,168의 방법에 따른 98%를 초과하는 광학 순도 상태로 얻어진다.By chemical synthesis from the precursor of (S); (S) Racemic mixtures of (S) enantiomers and 2-formylamino-2-phenyl-n-butyric acid are known and their preparations are described in sobotka et al. of Am. Chem. Soc., 54, 1932, p. 4697. In order to prepare such compounds, the advantages accepted by the method are that Bushier-Berg reacts with propiophenone with potassium cyanate and ammonium carbonate to give (+/-) 5-ethyl-5-phenylhydantoin. Which consists of stereospecific chlorides with (R) -α-methylbenzylamine in alkaline aqueous-acetone media to obtain addition salts of hydantoin with (S) enantiomers, insoluble salts yielding an acidic solution Filtration is removed by the used treatment, from which (S) 5-ethyl-5-phenylhydantoin is obtained in an optical purity of more than 98% according to the method of patent EP 0,510,168.
히단토인의 (S) 에난티오머는 통상적으로 알칼리성 수성 매질, 140℃의 온도에서 가수분해하여 (S) 2-아미노-2-페닐-n-부티르산을 얻고, N-포르밀화는 순수한 포름산과 아세트산 무수물을 반응시켜 (S) 2-포르밀아미노-2-페닐-n-부티르산 (III)을 얻는 것에 의해 수행된다.The (S) enantiomer of hydantoin is typically hydrolyzed at an alkaline aqueous medium, at a temperature of 140 ° C. to obtain (S) 2-amino-2-phenyl-n-butyric acid, and N-formylation is pure formic acid and acetic anhydride. Reaction to obtain (S) 2-formylamino-2-phenyl-n-butyric acid (III).
(R) 2-포르밀아미노-2-페닐-n-부티르산 및 (R,S)-2-포르밀아미노-2-페닐-n-부티르산은 개별적으로 5-에틸-5-페닐히단토인의 (R) 대장체 또는 (R,S) 라세메이트로부터 제조된다.(R) 2-formylamino-2-phenyl-n-butyric acid and (R, S) -2-formylamino-2-phenyl-n-butyric acid are individually selected from 5-ethyl-5-phenylhydantoin. R) colon or (R, S) racemates.
중간체 (III)의 카르복실 및 아미드 관능기를 동시에 환원시켜 각각 1급 알콜 관능기 및 2급 아민 관능기의 아미노 알콜 (II)을 얻는 것에 관하여, 제법은 문헌[Advanced Organic Chemistry p. 1095(J. March 3rd ed. 1985 McGraw Hill)]에 나타낸 요약표에 요약된 공지된 방법 및 시약으로 구성된다. 수소화 붕소 및 수소화 알루미늄의 유도체와 같은 환원제가 이러한 반응을 수행하는데 효과적인 것으로 권장되며, 특히 수소화 리튬 알루미늄 및 보란-디메틸 술파이드(이하 BSM이라 함) 착화물이 바람직한 시료이다.Regarding simultaneous reduction of the carboxyl and amide functional groups of intermediate (III) to obtain the amino alcohol (II) of the primary alcohol function and the secondary amine function, the preparation is described in Advanced Organic Chemistry p. 1095 (J. March 3rd ed. 1985 McGraw Hill), which consists of known methods and reagents summarized in the summary table. Reducing agents such as boron hydride and derivatives of aluminum hydride are recommended to be effective in carrying out this reaction, in particular lithium aluminum hydride and borane-dimethyl sulfide (hereinafter referred to as BSM) complexes are preferred samples.
환원은 디에틸 에테르, 디이소프로필 에테르, 1,2-디메톡시에탄 또는 테트라히드로푸란(THF)과 같은, 용매에서 해리되지 않는 비양성자성 매질에서 수행되는 것이 바람직하다.The reduction is preferably carried out in an aprotic medium that does not dissociate in a solvent, such as diethyl ether, diisopropyl ether, 1,2-dimethoxyethane or tetrahydrofuran (THF).
BMS 착화물은 환원될 생성물에 비례하여 화학량론적 과량으로 사용되어 반응을 완결한다. 따라서, 처리될 생성물의 몰당 2 내지 8 mol의 BMS가 사용되지만, 바람직한 양은 화합물 (II)당 4 내지 6 mol의 BMS이다.The BMS complex is used in stoichiometric excess in proportion to the product to be reduced to complete the reaction. Thus, although 2 to 8 mol of BMS per mole of product to be treated is used, the preferred amount is 4 to 6 mol of BMS per compound (II).
생성물은 습기로부터 보호되고 질소 분위기하에 THF의 용적 100부당 1 내지 10 중량부, 보다 구체적으로는 100중량부당 3 중량부 내지 7 중량부의 비율로 환원된다. 다량의 BMS가 공급된후, 혼합물을 환류하에 가열하여 30분 내지 10시간에서 반응을 완결하지만, 3 내지 5시간이 보다 유리하다. 아미노 알콜은 메탄올과 이후 수산화 나트륨을 가함으로써 환원제와 함께 그의 착화물로부터 방출시킨후 실시예에 기술한 통상적인 방법에 의해 최종적으로 단리시킨다.The product is protected from moisture and is reduced in a nitrogen atmosphere at a ratio of 1 to 10 parts by weight, more specifically 3 to 7 parts by weight, per 100 parts by weight of THF. After a large amount of BMS has been fed, the mixture is heated to reflux to complete the reaction in 30 minutes to 10 hours, but 3 to 5 hours is more advantageous. The amino alcohol is released from its complex with the reducing agent by addition of methanol and then sodium hydroxide and finally isolated by the conventional method described in the Examples.
(S) 전구체 (II)의 에스테르화에 관해서, 상기 나타낸 바와 같이 반응은 광범위하게 기술되어 있는, 예를 들면 벤젠, 톨루엔, 디에틸 에테르, 테트라히드로푸란, 디옥산, 아세톤, 아세토니트릴, 피리딘, 디메틸포름아미드, 메틸렌 클로라이드 또는 클로로포름과 같은 바람직한 비양성자성 무수 용매중에서 시료를 반응시키는 것으로 이루어진 다양한 기술[Sonntag, Chem. Rev. 52, 237-416 (1953) p. 312-324]에 따라서, 유토머성 아미노 에스테르 (I)을 얻기 위해 3,4,5-트리메톡시벤조일 클로라이드를 아미노 알콜 (II)로 가알콜분해하는 것으로 이루어진 공정 A에 의해 수행할 수 있다. 임의로는 산 수용체를 반응 매질에 가할 수 있다. 이러한 작용제는 무기 또는 유기물일 수 있다. 탄산 나트륨 또는 칼륨, 상응하는 탄산수소염 또는 트리에틸아민 또는 피리딘이 이러한 효과에 사용될 수 있다. 바람직한 별법은 동일 반응계내에서 알콜(II)의 금속 알콜화물을 예비 제조한후, 산염화물과 반응시키는 것으로 이루어져 있다. 금속 알콜화물은 나트륨과 같은 알칼리 금속 또는 그의 수소화물 또는 별법으로 그의 아미드의 작용으로 제조되거나, 불활성 상용 용매의 존재하에 나트륨 에톡시드 또는 칼륨 tert-부톡시드의 반응에 의해 제조된다. 예를 들면, 금속화 반응은 5 내지 20부의 THF 용액중 1 mol의 아미노 알콜 (II)과 0.9 내지 1.1 mol의 수소화 나트륨을 반응시키는 것으로 이루어지고, 알코올화물의 형성 반응은 일반적으로 1 내지 3시간 및 0 내지 67℃의 온도에서 완결된다.Regarding the esterification of (S) precursor (II), the reaction is broadly described as indicated above, for example benzene, toluene, diethyl ether, tetrahydrofuran, dioxane, acetone, acetonitrile, pyridine, Various techniques consisting of reacting a sample in a preferred aprotic anhydrous solvent such as dimethylformamide, methylene chloride or chloroform [Sonntag, Chem. Rev. 52, 237-416 (1953) p. 312-324, it can be carried out by process A, which consists of the alcoholic decomposition of 3,4,5-trimethoxybenzoyl chloride with amino alcohol (II) in order to obtain the eutomical amino ester (I). Optionally, acid acceptors can be added to the reaction medium. Such agents may be inorganic or organic. Sodium or potassium carbonate, the corresponding hydrogen carbonate or triethylamine or pyridine can be used for this effect. A preferred alternative consists of preliminarily preparing a metal alcoholate of alcohol (II) in situ, followed by reaction with an acid chloride. Metal alcoholates are prepared by the action of alkali metals such as sodium or their hydrides or alternatively their amides, or by reaction of sodium ethoxide or potassium tert-butoxide in the presence of an inert commercial solvent. For example, the metallization reaction consists of reacting 1 mol of amino alcohol (II) with 0.9 to 1.1 mol of sodium hydride in 5 to 20 parts of THF solution, and the formation reaction of alcoholate is generally 1 to 3 hours. And at a temperature of 0 to 67 ° C.
유토머성 아미노 에스테르 (I)는 1 mol의 (II) 또는 5 내지 20 부의 용매중 그의 알콜화물과 0.6 내지 1.8 mol의 3,4,5-트리메톡시벤조일 클로라이드를 반응시켜서 얻는다. 그러나, 1 mol의 (II) 또는 그의 알콜화물에 대한 바람직한 비율은 8 내지 15 부의 용매 및 0.8 내지 1.3 mol의 산염화물이다. 반응은 10 내지 110℃의 온도에서 1 내지 24시간 동안 계속한다. 바람직하게는, 20 내지 67℃에서 3 내지 7시간 동안 THF중에서 반응을 수행하면 에스테르 (I)을 만족스러운 수율로 얻을 수 있다. 화합물 (I)을 반응 매질로부터 단리시키고 추출, 결정화 및 칼럼 크로마토그래피와 같은 통상적인 방법에 의해 정제한다.Eutomeric amino esters (I) are obtained by reacting their alcoholates with 0.6 to 1.8 mol of 3,4,5-trimethoxybenzoyl chloride in 1 mol of (II) or 5 to 20 parts of solvent. However, the preferred ratio for 1 mol of (II) or its alcoholate is 8-15 parts of solvent and 0.8-1.3 mol of acid chloride. The reaction is continued for 1 to 24 hours at a temperature of 10 to 110 ° C. Preferably, the reaction (I) can be obtained in satisfactory yield by performing the reaction in THF at 20 to 67 ° C. for 3 to 7 hours. Compound (I) is isolated from the reaction medium and purified by conventional methods such as extraction, crystallization and column chromatography.
특히 바람직한 공정 B에 따라서, 메틸 3,4,5-트리메톡시벤조에이트를 아미노 알콜 (II)로 알콜분해하는 것은 산성 또는 염기성 촉매의 존재하에 무수 비양성자성 용매의 용액중에서 수행되는 에스테르교환반응에 의해 본 발명의 생성물 (I)을 얻게 한다. 공정 B가 바람직하며, 다른 한편으로 확대하면 알킬 라디칼이 1 내지 3개의 탄소 원자를 포함하는 3,4,5-트리메톡시벤조산 에스테르를 선택하여 에스테르교환반응에 의해 메틸, 에틸, 프로필 또는 이소프로필 알콜과 같은 낮은 비등점의 알콜을 얻고, 다른 한편으로는 반응 용매로서 벤젠, 톨루엔 또는 크실렌을 사용하여 이러한 알콜과 공비 혼합물을 형성하게 한다. 반응도중, 형성된 알콜을 제거하는 것이 유리하고, 이는 이러한 알콜을 격리하기 위한 적절한 다공성의 분자체와 같은 매질 작용제를 첨가하거나, 형성되는 대로 증류에 의해 제거한다. 이러한 에스테르교환반응 조건하에 메탄올을 생성하고 바람직한 반응 용매인 톨루엔과 함께 유리한 공비 혼합물을 생성하여 그들의 조성 및 그들의 비교적 높은 비등점으로 반응을 신속하게 진행하게 하는 메틸 3,4,5-트리메톡시벤조에이트를 사용하는 것이 특히 바람직하다. 산성 또는 염기성 촉매는 무기 및(또는) 유기물일 수 있다. 그러나 알칼리 또는 비알칼리성 금속 및, 예를 들면 칼륨 tert-부톡시드, 알루미늄 트리이소프로필레이트, 마그네슘 메톡시드, 나트륨, 수소화 나트륨, 나트륨 에톡시드 및 메톡시드와 같은 염기성 촉매가 바람직한데, 후자의 알콜화물이 특히 바람직하다.According to a particularly preferred process B, the alcoholysis of methyl 3,4,5-trimethoxybenzoate with amino alcohol (II) is carried out in a solution of anhydrous aprotic solvent in the presence of an acidic or basic catalyst. To give the product (I) of the present invention. Process B is preferred, while expanding on the other hand, methyl, ethyl, propyl or isopropyl by transesterification by selecting 3,4,5-trimethoxybenzoic acid esters having alkyl radicals containing from 1 to 3 carbon atoms Low boiling alcohols such as alcohols are obtained and on the other hand benzene, toluene or xylene are used as reaction solvents to form azeotropic mixtures with these alcohols. During the reaction, it is advantageous to remove the alcohol formed, which is added by the addition of a medium agent, such as a molecular sieve of a suitable porosity for sequestering this alcohol, or by distillation as it is formed. Methyl 3,4,5-trimethoxybenzoate, which produces methanol under these transesterification conditions and produces an advantageous azeotropic mixture with the preferred reaction solvent toluene to speed up the reaction to their composition and their relatively high boiling point. Particular preference is given to using. Acidic or basic catalysts can be inorganic and / or organic. However, alkali or non-alkaline metals and basic catalysts such as, for example, potassium tert-butoxide, aluminum triisopropylate, magnesium methoxide, sodium, sodium hydride, sodium ethoxide and methoxide are preferred, the latter alcoholates This is particularly preferred.
실제로, 반응은 10 내지 50 중량부의 적절한 용매에 1 mol의 아미노 알콜 (II)을 용해시킨후, 1.1 내지 2.0 mol의 벤조산 에스테르를 가하는 것으로 이루어진다. 0.025 내지 0.05 mol의 촉매를 가한후, 혼합물을 충분한 온도로 가열하고 증류에 의해 형성된 알콜 또는 그의 용매와의 공비 혼합물을 제거한다. 이 반응은 50 내지 130℃의 온도, 1 내지 6시간동안 수행하여 만족스러운 결과를 얻는다. 특히 바람직한 기술은 촉매를 반응도중 부분 또는 연속적으로 가하고, 또한 공비 증류의 경우에는 반응도중 용매를 가하여 증류에 의해 야기된 손실을 보상한다.In practice, the reaction consists of dissolving 1 mol of amino alcohol (II) in 10 to 50 parts by weight of a suitable solvent and then adding 1.1 to 2.0 mol of benzoic acid ester. After addition of 0.025 to 0.05 mol of catalyst, the mixture is heated to a sufficient temperature and the azeotropic mixture with the alcohol or its solvent formed by distillation is removed. This reaction is carried out for 1 to 6 hours at a temperature of 50 to 130 ° C. to obtain satisfactory results. A particularly preferred technique is to add the catalyst partly or continuously during the reaction and, in the case of azeotropic distillation, to add a solvent during the reaction to compensate for the losses caused by the distillation.
바람직한 조건은 1 mol의 아미노 알콜 (II), 1.25 내지 1.75 mol의 메틸 3,4,5-트리메톡시벤조에이트를 사용된 (II)의 양에 비례하여 25 내지 35 중량부의 톨루엔에 용해하는 것으로 이루어진다. 용액을 65 내지 75℃로 가열하고, 0.025 내지 0.05 mol의 나트륨 메톡시드를 가하고, 형성된 톨루엔-메탄올 공비 혼합물을 1 내지 2시간 동안 서서히 증류한다. 0.0125 내지 0.025 mol의 나트륨 메톡시드를 다시 가하고, 증류를 30분 내지 1시간 동안 수행하며 이러한 최종 작업을 다시 한 번 수행한다. 반응의 생성물을 단리하고 상기 언급된 기술에 따라서 정제한다.Preferred conditions are that 1 mol of amino alcohol (II), 1.25-1.75 mol of methyl 3,4,5-trimethoxybenzoate are dissolved in 25-35 parts by weight of toluene in proportion to the amount of (II) used. Is done. The solution is heated to 65-75 ° C., 0.025-0.05 mol sodium methoxide is added and the toluene-methanol azeotrope formed is slowly distilled for 1-2 hours. 0.0125 to 0.025 mol of sodium methoxide is added again, distillation is carried out for 30 minutes to 1 hour and this final operation is carried out once again. The product of the reaction is isolated and purified according to the techniques mentioned above.
본 발명은 상기 언급된 공정 A 및 B를 나타내는 하기 실시예에 의해서 비제한적으로 예시된다.The present invention is exemplified non-limitingly by the following examples representing the processes A and B mentioned above.
본 발명의 생성물의 순도, 확인 및 물리화학적 특성을 측정하였다Purity, identification and physicochemical properties of the products of the present invention were measured.
- 순도는 실리카겔상에서 박층 크로마토그래피에 의해 검사하였다. 사용된 용출 용매중에서 관찰된 Rf를 실시예에 나타낸다.Purity was checked by thin layer chromatography on silica gel. Rf observed in the elution solvent used is shown in the examples.
- 제안된 구조로 얻어진 생성물의 확인은 400 MHz에서 그들의 양성자 핵 자기 공명 스펙트럼에 의해 검사되며, 생성물은 내부 표준으로서 테트라메틸 실란과 함께 듀테로클로로포름에 용해된다. 신호의 특성인 ppm으로의 그들의 화학적 이동 뿐만 아니라 그들이 나타내는 양성자의 수가 기록된다.Identification of the product obtained with the proposed structure is examined by their proton nuclear magnetic resonance spectra at 400 MHz, and the product is dissolved in deuterochloroform with tetramethyl silane as internal standard. The number of protons they represent, as well as their chemical shift to ppm, a characteristic of the signal, is recorded.
- 고체 형태로 얻어진 생성물에 대하여, 시차열분석에 의해 얻어진 융점의 값을 나타낸다.For products obtained in solid form, the melting point values obtained by differential thermal analysis are shown.
하기 실시예의 기술적인 설명은 본 발명의 범위를 예시하지만 그를 제한하는 것은 아니다.The technical description of the following examples illustrates the scope of the invention but is not limiting thereof.
a) - 화학적 성질a)-chemical properties
<실시예 1><Example 1>
(s) 2-메틸아미노-2-페닐-n-부틸 3,4,5-트리메톡시벤조에이트 (I)(s) 2-methylamino-2-phenyl-n-butyl 3,4,5-trimethoxybenzoate (I)
- 단계 1: (S) 2-메틸아미노-2-페닐-n-부탄올 (II)Step 1: (S) 2-methylamino-2-phenyl-n-butanol (II)
1375 ml의 무수 테트라히드로푸란(THF)중 55.0 g(0.27 mol)의 (S) 2-포르밀아미노-2-페닐-n-부티르산(α20 D= + 123°, c = 1 NaOH N)을 습기로부터 보호되고 질소 분위기하의 반응기에 공급했다. 125.9 ml, 즉 100.8 g(1.33 mol)의 보란디메틸 술파이드 착화물을 20℃에서 교반하며 1시간 동안 현탁액에 가했다. 공급후, 얻은 용액을 가열하고 4시간 동안 환류하며 유지시켰다.55.0 g (0.27 mol) of (S) 2-formylamino-2-phenyl-n-butyric acid (α 20 D = + 123 °, c = 1 NaOH N) in 1375 ml of anhydrous tetrahydrofuran (THF) Protected from moisture and fed to the reactor under nitrogen atmosphere. 125.9 ml, or 100.8 g (1.33 mol) of boranedimethyl sulfide complex, were added to the suspension for 1 hour with stirring at 20 ° C. After feeding, the resulting solution was heated and maintained at reflux for 4 hours.
이 현탁액을 0 내지 5℃로 냉각시키고 200 ml의 메탄올을 10℃가 넘지않도록 가한후, 동일 조건하에 220 ml의 10% NaOH 용액을 가했다.The suspension was cooled to 0-5 ° C. and 200 ml of methanol was added no more than 10 ° C., followed by the addition of 220 ml of 10% NaOH solution under the same conditions.
혼합물을 1시간 동안 20 내지 25℃로 교반한후, 용매를 물 배스상에서 진공 증류하여 제거하였다. 잔사를 1250 ml의 물로 취하고, 0℃로 냉각시킨후 교반하며 약 40 ml의 농축 염산을 사용하여 pH 1로 산성화하였다.The mixture was stirred for 1 h at 20-25 [deg.] C. and then the solvent was removed by vacuum distillation on a water bath. The residue was taken up with 1250 ml of water, cooled to 0 ° C. and stirred and acidified to pH 1 with about 40 ml of concentrated hydrochloric acid.
산성상을 220 ml의 메틸-t-부틸 에테르로 5회 추출한후, 10℃ 미만에서 교반하며 26.5 g의 NaOH 펠렛을 첨가하여 염기성화하였다.The acidic phase was extracted five times with 220 ml of methyl-t-butyl ether and then basified by addition of 26.5 g of NaOH pellet with stirring below 10 ° C.
혼합물을 170 ml의 디클로로메탄으로 3회 추출하였다. 배합된 유기상을 물로 세척하고 Na2SO4로 탈수화하고 용매를 진공 증류하여 제거하였다. 조질의 생성물을 다음 단계에서 사용되기에 충분한 정도의 크로마토그래피 순도로 얻었다.The mixture was extracted three times with 170 ml of dichloromethane. The combined organic phases were washed with water, dehydrated with Na 2 SO 4 and the solvent was removed by vacuum distillation. The crude product was obtained with a degree of chromatographic purity sufficient for use in the next step.
중량 = 35.3 g Y = 74.2%Weight = 35.3 g Y = 74.2%
TLC: Rf 0.50-0.60 (부탄올-아세트산-물 8-2-2 v/v/v)TLC: Rf 0.50-0.60 (butanol-acetic acid-water 8-2-2 v / v / v)
[α]20 D= +13.6° (c = 2, HCl N)[α] 20 D = + 13.6 ° (c = 2, HCl N)
-1H - NMR δ(ppm): 0.70 (t, 3H); 1.55-1.65 (m, 1H); 1.75-1.85 (m, 1H); 2.15 (s, 3H); 2.20-2.40 (m, 2H); 3.70-3.85 (m, 2H); 7.20-7.30 (m, 3H); 7.35-7.50 (m, 2H) 1 H-NMR δ (ppm): 0.70 (t, 3H); 1.55-1.65 (m, 1 H); 1.75-1.85 (m, 1 H); 2.15 (s, 3 H); 2.20-2.40 (m, 2 H); 3.70-3.85 (m, 2 H); 7.20-7.30 (m, 3H); 7.35-7.50 (m, 2H)
- IR (필름 - NaCl 펠렛): 3300, 2900, 1600, 1490, 1440, 1380, 1330, 1130, 1040, 1010, 840, 760, 700 cm-1 IR (Film-NaCl Pellets): 3300, 2900, 1600, 1490, 1440, 1380, 1330, 1130, 1040, 1010, 840, 760, 700 cm -1
- 단계 2: (S) 2-메틸아미노-2-페닐-n-부틸 3,4,5-트리메톡시벤조에이트 (I)Step 2: (S) 2-methylamino-2-phenyl-n-butyl 3,4,5-trimethoxybenzoate (I)
방법 AMethod A
미네랄 오일중 7.03 g의 60%(w/w) 수소화 나트륨의 현탁액(즉, 4.22 g - 0.176 mol의 순수한 생성물)을 습기로부터 보호되고 질소 분위기하의 반응기중 42 ml의 무수 THF에 공급했다. 현탁액을 교반하며 환류 가열하고, 21 ml의 THF중 30.0 g의 (S) 2-메틸아미노-2-페닐-n-부탄올 (II) 용액을 약 30분 동안 점적하였다.A suspension of 7.03 g of 60% (w / w) sodium hydride (ie, 4.22 g-0.176 mol of pure product) in mineral oil was fed to 42 ml of dry THF in a reactor under nitrogen atmosphere and protected from moisture. The suspension was heated to reflux with stirring and 30.0 g of (S) 2-methylamino-2-phenyl-n-butanol (II) solution in 21 ml of THF was added dropwise for about 30 minutes.
혼합물을 1시간 동안 환류하며 유지시킨후, 89 ml의 THF 중 농도 98%인 43.3 g(0.184 mol)의 3,4,5-트리메톡시벤조일 클로라이드를 약 1시간 동안 50 내지 60℃에서 가했다. 첨가후, 혼합물을 2시간 동안 환류하며 유지시킨후 110 ml의 THF를 보통 압력에서 증류 제거하고, 105 ml의 톨루엔을 농축된 매질에 가하고, 20℃로 냉각시킨후 60 ml의 물을 가했다. 15분 동안 교반한 후, 유기상을 225 ml의 물중 9.0 ml의 93% H2SO4용액으로 산성화하고, 산성상을 분리시키고, 냉각 상태에서 33 ml의 30% NaOH 용액으로 염기성화한후 100 ml의 디클로로메탄으로 3회 추출했다. 배합된 유기상을 물로 세척하고, Na2SO4로 탈수화한후, 용매를 진공 증류하여 제거하였다. 잔사를 250 ml의 헥산으로 50℃에서 취했다. 냉각중 기대한 화합물이 결정화하였다. 2시간 동안 10℃에서 교반한후, 생성물을 여과하고 건조시켰다.After maintaining the mixture at reflux for 1 hour, 43.3 g (0.184 mol) of 3,4,5-trimethoxybenzoyl chloride at 98% concentration in 89 ml of THF was added at 50-60 ° C. for about 1 hour. After addition, the mixture was kept at reflux for 2 hours before 110 ml of THF was distilled off at normal pressure, 105 ml of toluene was added to the concentrated medium, cooled to 20 ° C. and 60 ml of water was added. After stirring for 15 minutes, the organic phase is acidified with 9.0 ml of 93% H 2 SO 4 solution in 225 ml of water, the acidic phase is separated, basified with 33 ml of 30% NaOH solution in cold state and then 100 ml Extracted three times with dichloromethane. The combined organic phases were washed with water, dehydrated with Na 2 SO 4 and then the solvent was removed by vacuum distillation. The residue was taken up at 50 ° C. with 250 ml of hexane. The expected compound crystallized during cooling. After stirring at 10 ° C. for 2 hours, the product was filtered and dried.
중량 = 37.2 g Y = 59.5% m.p. = 46℃Weight = 37.2 g Y = 59.5% m.p. = 46 ° C
TLC: Rf 0.10-0.20 (톨루엔-아세톤 9-1 v/v)TLC: Rf 0.10-0.20 (toluene-acetone 9-1 v / v)
[α]20 D= 4% 에탄올성 용액에 대한 10 cm 편광계 관에서 의미 없음[α] 20 D = meaningless in 10 cm polarimeter tubes for 4% ethanol solution
- HPLC에 의해 측정된 광학 순도가 99%를 초과함-Optical purity measured by HPLC exceeds 99%
-1H - NMR δ(ppm): 0.80 (t, 3H); 1.50-1.70 (m, 1H); 1.80-1.95 (m, 2H); 2.25 (s, 3H); 3.80(s, 6H); 3.90 (s, 3H); 4.50-4.65 (m, 2H); 7.15 (s, 2H); 7.20-7.25 (m, 1H); 7.30-7.40 (m, 2H); 7.50-7.55 (m, 2H) 1 H-NMR δ (ppm): 0.80 (t, 3H); 1.50-1.70 (m, 1 H); 1.80-1.95 (m, 2 H); 2.25 (s, 3 H); 3.80 (s, 6 H); 3.90 (s, 3 H); 4.50-4.65 (m, 2 H); 7.15 (s, 2 H); 7.20-7.25 (m, 1 H); 7.30-7.40 (m, 2 H); 7.50-7.55 (m, 2H)
- IR (KBr 펠렛): 2800, 1710, 1590, 1500, 1460, 1410, 1360, 1330, 1220, 1180, 1120, 1000, 760, 700 cm-1 IR (KBr pellet): 2800, 1710, 1590, 1500, 1460, 1410, 1360, 1330, 1220, 1180, 1120, 1000, 760, 700 cm -1
<실시예 2><Example 2>
(S) 2-메틸아미노-2-페닐-n-부틸 3,4,5-트리메톡시벤조에이트 (I)(S) 2-methylamino-2-phenyl-n-butyl 3,4,5-trimethoxybenzoate (I)
방법 B (바람직한 방법)Method B (preferred method)
습기로부터 보호되고 질소 분위기하의 반응기 중에서 440 ml의 무수 톨루엔 및 22 ml의 순수한 에탄올의 혼합물에In a mixture of 440 ml of anhydrous toluene and 22 ml of pure ethanol in a reactor protected from moisture and in a nitrogen atmosphere.
- 실시예 1의 단계 1과 같이 제조된 10.0 g(0.056 mol)의 (S) 2-메틸아미노-2-페닐-n-부탄올10.0 g (0.056 mol) of (S) 2-methylamino-2-phenyl-n-butanol prepared as in Step 1 of Example 1
- 19.0 g(0.084 mol)의 메틸 3,4,5-트리메톡시벤조에이트를 공급했다.19.0 g (0.084 mol) of methyl 3,4,5-trimethoxybenzoate were fed.
용액을 교반하며 가열하고, 보통 압력하에 110 ml의 용매의 혼합물을 증류 제거하였다. 100℃로 냉각시킨후, 180 ml의 무수 톨루엔 및 2.7 ml의 4 N 나트륨 메톡시드의 메탄올성 용액을 가했다. 혼합물을 가열하고, 150 ml의 용매를 1시간 동안 증류 제거한 후, 혼합물을 100℃로 냉각시키고 150 ml의 무수 톨루엔 및 0.9 ml의 4 N 나트륨 메톡시드 용액을 가하고, 혼합물을 가열하여 140 ml의 용매를 1시간 동안 증류 제거하고, 100℃로 냉각시키고 톨루엔 및 메톡시드의 첨가를 반복하여 1시간 동안 120 ml의 용매를 최종적으로 증류 제거하였다.The solution is heated with stirring and the mixture of 110 ml of solvent is distilled off under normal pressure. After cooling to 100 ° C., methanolic solution of 180 ml of anhydrous toluene and 2.7 ml of 4N sodium methoxide was added. The mixture is heated and 150 ml of solvent is distilled off for 1 hour, then the mixture is cooled to 100 ° C. and 150 ml of anhydrous toluene and 0.9 ml of 4 N sodium methoxide solution are added and the mixture is heated to 140 ml of solvent Was distilled off for 1 hour, cooled to 100 ° C. and the addition of toluene and methoxide was repeated to finally distill off 120 ml of solvent for 1 hour.
반응 혼합물을 진공하에 농축시키고, 잔사를 120 ml의 1N HCl로 취하고, 혼합물을 70 ml의 디클로로메탄으로 3회 추출하였다. 배합된 유기상을 세척 및 건조한후, 용매를 진공하에 증발시켰다. 오일성 잔사(17.6 g)을 실리카 칼럼상에서 신속한 크로마토그래피에 의해 정제하였다. 디클로로메탄-아세톤 95-5(v/v) 혼합물로 용출하여 순수한 상태의 생성물을 얻을 수 있었다.The reaction mixture was concentrated in vacuo, the residue was taken up with 120 ml of 1N HCl and the mixture was extracted three times with 70 ml of dichloromethane. After washing and drying the combined organic phases, the solvent was evaporated in vacuo. The oily residue (17.6 g) was purified by rapid chromatography on a silica column. Elution with a dichloromethane-acetone 95-5 (v / v) mixture gave the pure product.
중량 = 15.6 g 수율 = 74.6%Weight = 15.6 g Yield = 74.6%
실시예 1의 단계 2에서 얻은 생성물에 대한 것과 일치하게 분석하였다.The analysis was made consistent with that for the product obtained in step 2 of Example 1.
<실시예 3><Example 3>
(S) 2-메틸아미노-2-페닐-n-부틸 3,4,5-트리메톡시벤조에이트 L(+)-타르트레이트 (I)(S) 2-methylamino-2-phenyl-n-butyl 3,4,5-trimethoxybenzoate L (+)-tartrate (I)
15.0 g(0.040 mol)의 (S) 2-메틸아미노-2-페닐-n-부틸 3,4,5-트리메톡시벤조에이트 및 6.03 g(0.040 mol)의 L(+)-타르타르산을 반응기중 150 ml의 순수한 에탄올에 가했다.15.0 g (0.040 mol) of (S) 2-methylamino-2-phenyl-n-butyl 3,4,5-trimethoxybenzoate and 6.03 g (0.040 mol) of L (+)-tartaric acid in a reactor It was added to 150 ml of pure ethanol.
혼합물을 가열하고, 교반하며 5분 동안 환류하에 유지하였다. 50 ml의 에탄올을 보통 압력에서 증류 제거한후, 1 ml의 물을 적가하였다.The mixture was heated, stirred and kept under reflux for 5 minutes. 50 ml of ethanol were distilled off at normal pressure, then 1 ml of water was added dropwise.
냉각중 염이 결정화되었다. 혼합물을 15 내지 20℃에서 4시간 동안 방치한후, L(+)-타르트레이트 일수화물 결정을 여과 제거하고 건조하였다.Salts crystallized during cooling. The mixture was left at 15-20 ° C. for 4 hours, after which the L (+)-tartrate monohydrate crystals were filtered off and dried.
중량 = 16.0 g 수율 = 73.9%Weight = 16.0 g Yield = 73.9%
m.p. = 94 - 97℃m.p. = 94-97 ° C
C21H27NO2, C4H6O6·H2O와 일치한 분석.Analysis consistent with C 21 H 27 NO 2 , C 4 H 6 O 6 .H 2 O.
이러한 실시예의 방법에 따라서,According to the method of this embodiment,
a) (R,S) 2-메틸아미노-2-페닐-n-부틸 3,4,5-트리메톡시벤조에이트 및 그의 헤미말레에이트(m.p. = 138℃),a) (R, S) 2-methylamino-2-phenyl-n-butyl 3,4,5-trimethoxybenzoate and hemimaleate thereof (m.p. = 138 ° C),
b) (R) 2-메틸아미노-2-페닐-n-부틸 3,4,5-트리메톡시벤조에이트 및 D(-)-타르타르산과의 무수염(m.p. = 132℃)이 (R,S) 또는 (R) 2-메틸아미노-2-페닐-n-부티르산으로 출발하여 개별적으로 제조된다.b) Anhydrous salts with (R) 2-methylamino-2-phenyl-n-butyl 3,4,5-trimethoxybenzoate and D (-)-tartaric acid (mp = 132 ° C.) yield (R, S Or (R) prepared separately starting with 2-methylamino-2-phenyl-n-butyric acid.
b) 시험관내 수용체 연구b) in vitro receptor studies
본 연구는 (S), (R) 에난티오머 및 용액중 μ, δ 및 κ 마취성 수용체에 대한 그들의 염의 형태인 그들의 라세미 혼합물의 개별적인 친화도를 평가하는 것으로 이루어진 연구를 그들의 라세미 전구체인 트리메부틴 TMB와 비교하여 수행하였다.This study consisted of evaluating the individual affinity of (S), (R) enantiomers and their racemic mixtures in the form of their salts for μ, δ and κ anesthetic receptors in solution with their racemic precursors It was performed in comparison to trimebutin TMB.
시험은 각 수용체에 대한 적절한 제법으로 로만(F. Roman)등의 문헌[J. Pharm. Pharmacol. (1987), 39, p. 404-407]에 기술된 기술을 채용하여 각 아유형에 특정한 방사성 리간드와 화합물의 친화도를 경쟁시키는 것으로 이루어져 있고, 적절한 농도의 시험 화합물의 용액을 방사성 리간드가 적재된 제제를 함께 배양하여 방사선 리간드를 경쟁시키고 치환한후, 여과하고 방사능을 측정하는 것으로 이루어졌다.Tests are described in F. Roman et al. [J. Pharm. Pharmacol. (1987), 39, p. 404-407, which employs the techniques described in the present article to compete with the affinity of a compound with a radioligand specific for each subtype, and incubates a solution of the test compound in an appropriate concentration with a radioligand loaded formulation. After competing and replacing, filtration and radioactivity.
즉, μ수용체에 대한 친화도의 측정을 위해서, [3H]-DAGO로 예비 배양된 쥐 뇌막의 현탁액을 사용하고, δ수용체에 대한 친화도의 측정을 위해서, [3H]-DADLE로 예비 배양된 기니아 피그 뇌막의 현탁액을 사용하고, κ수용체에 대한 친화도의 측정을 위해서, [3H]-U69,593으로 예비 배양된 rKOR-CHO 세포를 사용하였다. 각 실험을 위해, 여과된 방사능이 측정된후, 결과를 컴퓨터 처리하여 50%의 방사능 리간드에 대한 억제 상수를 계산하고 nM중 Ki 값으로 나타냈다. 연구 결과를 하기 표에 나타낸다.That is, in order to measure the affinity for the μ receptor, [3 H] using a suspension of the pre-culture into rats -DAGO meninges, to the measurement of the affinity for the δ receptor, and [3 H] Preliminary in -DADLE Suspensions of cultured guinea pig meninges were used, and rKOR-CHO cells pre-cultured with [ 3 H] -U69,593 were used for determination of affinity for the κ receptor. For each experiment, after the filtered radioactivity was measured, the results were computerized to calculate the inhibition constant for the 50% radioligand and expressed as the Ki value in nM. The results of the study are shown in the table below.
친화도는 이러한 시험에서 마취성 아유형을 고려할 필요없이 유토머인 (R) 에난티오머에 대한 입체특이성의 증거이고, 유디즘 비율 (Ki (S)/Ki (R))의 역수가 각각 μ 아유형에 대해 2.7, δ 아유형에 대해 3.3, κ 아유형에 대해 2.6이었다. 또한, 친화도의 감소는 전체적으로 특히 그들의 생물학적 전구체인 라세미 TMB와 비교하여 NDTMB의 δ, κ 아유형 및 그의 에난티오머에서 관찰되었다.Affinity is evidence of stereospecificity for the utomeric (R) enantiomer, without having to consider anesthetic subtypes in these tests, and the inverse of the judicial ratio (Ki (S) / Ki (R)) 2.7 for the subtype, 3.3 for the δ subtype, and 2.6 for the κ subtype. In addition, a decrease in affinity has been observed overall in the δ, κ subtypes of NDTMB and its enantiomers, especially compared to their biological precursors, racemic TMB.
c) 진통제 활성: 생체내 연구c) analgesic activity: in vivo studies
이러한 시험에서, 생성물은 염화된 형태, 즉 (S) 및 (R) 에난티오머에 대한 타르트레이트 형 및 라세미 NDTMB에 대한 말레에이트 형으로 사용되었다.In this test, the product was used in chlorinated form, namely the tartrate form for (S) and (R) enantiomers and the maleate form for racemic NDTMB.
c.1) - (R), (S) 에난티오머 및 그들의 라세미 혼합물 NDTMB의 비교 활성c.1)-Comparative activity of (R), (S) enantiomers and their racemic mixture NDTMB
이 활성은 만성 통증의 대표적인 것으로 인식되는 시험으로 평가되었다.This activity was evaluated in tests that were recognized as representative of chronic pain.
- 마우스의 다리에 포름알데히드 용액을 주입함으로써 야기되는 지발 강직성 통증 현상에 대한 진통 활성,Analgesic activity against late stiffness pain caused by injecting formaldehyde solution into the legs of the mouse,
- 쥐의 PGE2에 의해 유도되는 만성 통각과민에 대한 진통 활성Analgesic activity against chronic hyperalgesia induced by rat PGE2
c.1.1) - 마우스의 포름알데히드 시험c.1.1)-formaldehyde test in mice
이 기술은 훈스카(S. Hunskarr)의 문헌[J. of Neurosciences Methods, 1985, 14, p. 69-76]에 기술된 것을 채용하고, 동물의 다리 한 쪽의 발바닥 내부로 20 ㎕의 5% (v/v) 살균 식염수 포름알데히드 용액을 주입하여 고통을 주는 염증을 야기하는 것으로 이루어져 있다. 동물이 처리된 다리를 핥는 반응의 지속 시간은 시험의 t0로 여겨지는 포르말린의 주입후, 20 내지 25분 정도이다.This technique is described in S. Hunskarr [J. of Neurosciences Methods, 1985, 14, p. 69-76, which consists of injecting 20 μl of 5% (v / v) sterile saline formaldehyde solution into the sole of one animal leg to cause painful inflammation. The duration of the reaction for the animal to lick the treated leg is on the order of 20 to 25 minutes after infusion of formalin, considered to be the test's t0.
생성물의 활성을 평가하기 위해, 포르말린의 발바닥 내부 주입 10분 전 예비 처리로서 1 ㎖/100 g의 양으로 피하 투여된다. 시험물질의 마취성 성분을 조사하는 시험에서, 용액중 1 mg/kg의 날옥손이 포르말린의 투여 5분후, 즉 시험 생성물의 피하 투여 15분후 피하 투여된다. 처리된 동물의 배치에 대한 시간과 비히클을 수용한 배치에 대한 시간을 비교하는 것은 % 진통 활성으로 나타내는 결과를 측정할 수 있게한다.To assess the activity of the product, it is administered subcutaneously in an amount of 1 ml / 100 g as a pretreatment 10 minutes before the plantar infusion of formalin. In tests examining the anesthetic component of the test substance, 1 mg / kg naloxone in solution is administered subcutaneously 5 minutes after formalin, ie 15 minutes after subcutaneous administration of the test product. Comparing the time for the batch of treated animals with the time for the batch that received the vehicle makes it possible to determine the result, expressed as% analgesic activity.
이러한 결과는 앞선 시험관내 연구로 미루어보아 하기 두 가지 관점에서 본 발명의 (S) 에난티오머의 특별히 유리한 활성의 증거가 된다.These results are evidence of the particularly advantageous activity of the (S) enantiomer of the present invention in light of the above in vitro studies.
i) (S) 에난티오머는 실질적으로 라세메이트와 동일하지만, 어떠한 경우에서도 (R) 대장체의 그것을 초과하지 않는 활성을 나타내고,i) the (S) enantiomer is substantially the same as the racemate, but in any case exhibits an activity that does not exceed that of the (R) colon;
ii) 날옥손에 의하여 (R,S) 라세메이트 및 (R) 대장체 모두가 진통 활성이 현저하게 억제되는 반면, (S) 에난티오머에 관해서는 변화하지 않으며, 이는 만성 통증과 관련된 시험 조건하에 비교되는 생성물과는 상이한 비-마취성 메카니즘에 의해 작용하는 화합물을 제시한다.ii) both (R, S) racemate and (R) colon are significantly inhibited in analgesic activity by naloxone, but do not change with respect to (S) enantiomers, which are test conditions associated with chronic pain. Compounds that act by non-anesthetic mechanisms different from the products compared below are presented.
c.1.2) - 쥐의 PGE2에 의해 유도되는 만성 통각과민에 대한 진통 활성c.1.2)-analgesic activity against chronic hyperalgesia induced by PGE2 in rats
본 시험은 랜달(Randall) 및 셀리토(Selitto) 시험에 의해 나카무라-크레이그(M. Nakamura-Craig) 등의 문헌[Pain, 63, (1995) 33-37]에 기술된 것을 채용한 프로토콜에 따라서 4일 동안 다리에 PGE2의 발바닥내 주입에 의해 야기된 만성 통각과민에 있어서의 시험 화합물의 진통 효과를 측정하는 것으로 이루어져 있다.This test was carried out by the Randall and Selitto test according to the protocol employing the one described in M. Nakamura-Craig et al. (Pain, 63, (1995) 33-37). It consists of measuring the analgesic effect of the test compound on chronic hyperalgesia caused by intraplantar injection of PGE2 into the legs for 4 days.
특히, 본 연구는 120 내지 140 g의 스프라그-돌리(Sprague-Dawley) 쥐에게 일일 2회씩 연속 4일 동안 발바닥 내부에 100 ㎕의 용적으로 100 ng의 PGE2를 투여하는 배치로 수행되고, 이는 5일째 날부터 만성 통각과민을 야기하며 적어도 일주일간 유지된다. 시험 당일 오전에, 통증에 대한 반응 발단을 랜달 및 셀리토 시험에 의해 검사하고, 발단이 독단적으로 정의된 110 이하인 동물을 선택한후, 오후에 시험 생성물의 용액을 피하 경로로 예비 투여후 측정을 반복한다. 이러한 투여를 통증 발단의 측정 30 분전에 수행한다. 치료 이전 및 이후에 측정된 발단의 평균을 각 배치에 대하여 계산하고, 단지 시험 생성물에 대한 비히클만을 수용한 동물과 비교하여 % 진통 활성으로 결과를 측정할 수 있게 한다.In particular, the study was conducted in a batch of 120-140 g Sprague-Dawley rats administered 100 ng of PGE2 in a volume of 100 μl inside the sole of the foot for four consecutive days twice daily, which was 5 From day one it causes chronic hyperalgesia and persists for at least a week. On the morning of the test day, the onset of response to pain is examined by the Randall and Celito test, an animal whose incidence is arbitrarily defined as 110 or less is selected, and in the afternoon the measurement of the test product is repeated after a subcutaneous administration of the test product subcutaneously. do. This administration is performed 30 minutes before the measurement of pain incidence. The average of incidences measured before and after treatment is calculated for each batch and results can be measured in% analgesic activity compared to animals that only received vehicle for the test product.
첫번째 일련의 시험에서, 증가하는 분량의 투여는 (R), (S) 에난티오머 및 그들의 라세미 혼합물 NDTMB의 비교 활성을 측정할 수 있게 했다. 두번째 일련의 시험에서, 날옥손이 존재하거나 존재하지 않는 단일 분량으로 투여되는 생성물은 관찰된 효과에 있어서 마취성분의 참여를 측정할 수 있게 했다. 이러한 시험의 결과를 하기 표에 % 진통 활성으로 나타냈다.In the first series of trials, increasing doses allowed to measure the comparative activity of (R), (S) enantiomers and their racemic mixture NDTMB. In a second series of trials, the product administered in a single dose, with or without naloxone, allowed to measure the involvement of the anesthetic in the observed effects. The results of these tests are shown as% analgesic activity in the table below.
NT : 시험되지 않음NT: not tested
이러한 시험은 그의 대장체 및 라세미 혼합물과 비교하여 본 발명의 (S) 유토머의 진통 활성의 증거이지만, 특히 날옥손의 존재하에 67%의 활성이 유지되기 때문에 마취 효과에 단지 약간만 영향을 받는 반면, 다른 두 화합물에 대해서는 날옥손이 마취 메카니즘에 기인하는 전체 활성을 실질적으로 억제한다.This test is evidence of the analgesic activity of the (S) utomer of the present invention compared to its colon and racemic mixtures, but only slightly affected by the anesthetic effect, since 67% of the activity is maintained, especially in the presence of naloxone On the other hand, for the other two compounds, naloxone substantially inhibits the overall activity attributable to the anesthetic mechanism.
c.2) - 만성 통증의 다양한 대표적 모델에 대한 (S) 유토머의 활성c.2)-(S) utomer activity on various representative models of chronic pain
- 당뇨병 쥐에 있어서 통각과민 모델에 대한 활성Activity against hyperalgesia model in diabetic rats
본 시험은 부르키엘(Burchiel) 등의 문헌[Diabetes, 34 (1985) 1210-1213]에 기술된 기술에 따라서 수행되고, 이는 동물에 있어서 스트렙토조톡신을 주입하여 실험 당뇨병을 야기하고, 당뇨 조건 및 통각과민을 확인하고, 시험 화합물의 진통 효과를 측정하기 위한 시험을 수행하는 것으로 이루어져 있다. 이러한 측정은 44℃로 유지되는 물 배스에 동물의 꼬리를 넣음으로써 수행되고, 고온의 물 배스로부터 꼬리를 치우기 전까지의 시간을 측정함으로써 통증에 대한 반응을 측정한다. 이러한 시험에서, 피하 경로로 투여된 본 발명의 (S) 유토머는 30 mg/kg의 투여량에서 진통 활성을 나타낸다.This test is performed according to the technique described in Burchiel et al., Diabetes, 34 (1985) 1210-1213, which induces experimental diabetes by injecting streptozotoxin in animals, It consists of performing tests to identify hyperalgesia and to determine the analgesic effect of the test compound. This measurement is performed by placing the animal's tail in a water bath maintained at 44 ° C. and measures the response to pain by measuring the time before removing the tail from the hot water bath. In this test, the (S) utomer of the invention administered by the subcutaneous route shows analgesic activity at a dose of 30 mg / kg.
- 신경장해적 통증에 대한 활성-Activity against neuropathic pain
베넷(Bennett) 및 지에(Xie) 기술에 따라서 좌골 신경의 느슨한 결찰에 의해 쥐에 있어서 단일신경장애 모델을 생성하고, 시험 화합물의 효과를 캐더린(G. Catherine) 등의 문헌[European Journal of Pharmacology, 318 (1996) 273-281]에 기술된 기술에 따른 U. 바실(U. Basile) 진통계의 보조로 랜달 및 셀리토 방법을 개질하여 측정한다. 이러한 시험에서, 본 발명의 (S) 유토머는 피하 경로에 의한 1 mg/kg의 투여량으로부터 활성을 나타내고, 이러한 효과는 날옥손에 의해 개질되지 않은 것이다.According to Bennett and Xie techniques, a single neuropathy model is generated in mice by loose ligation of the sciatic nerve and the effect of the test compound is described by G. Catherine et al., European Journal of Pharmacology, 318 (1996) 273-281, measured by modifying the Randall and Celito methods with the aid of the U. Basile analgesic system according to the technique described. In this test, the (S) utomers of the present invention show activity from a dose of 1 mg / kg by the subcutaneous route, and this effect is not modified by naloxone.
- 행동 통증에 대한 활성-Active against behavioral pain
본 시험은 진찰시 통증을 일으키는 위치의 뒷다리에 카라제닌을 주입함으로써 야기되는 지속 통증이 있는 쥐를 사용하여 수행된다. 동물에 있어 시험 생성물의 가능한 진통 효과를 정성 및 정량적으로 분석이 가능하게 하는 상이한 행동 변수가 관찰된다. 이러한 시험에서, (S) 유토머는 피하 경로에 의한 3 mg/kg의 투여량으로부터 활성을 나타낸다.This test is performed using rats with persistent pain caused by injecting carrageenin into the hind limbs of the site causing pain upon examination. Different behavioral variables are observed in animals that allow for qualitative and quantitative analysis of possible analgesic effects of test products. In this test, (S) utomers show activity from a dose of 3 mg / kg by subcutaneous route.
c.3) - 마취 의존성 효과의 평가 : 새렌스 시험(Saelens test)c.3)-Evaluation of anesthetic dependence effect: Saelens test
새렌스(J.K. Saelens) 등의 문헌[Arch. Int. Pharmacodyn. (1971)]에 따른 본 시험은 추정의 마취성 생성물의 반복되는 투여후 날옥손의 투여로써 마우스에게 중독을 야기하고, 갑작스러운 중단으로, 특히 주어진 경과 시간동안 시험생성물의 작용하에 동물에 있어서 몰핀 형 상태의 의존성을 반영하는 경련의 횟수와 같은 특징적인 반응을 야기하는 것으로 이루어져 있다.J.K. Saelens et al. Arch. Int. Pharmacodyn. (1971), according to the present study, induces poisoning in mice by administration of naloxone after repeated administration of putative anesthetic products, and sudden abort, especially morphine in animals under the action of the test product for a given elapsed time. It is composed of causing characteristic reactions such as the number of convulsions that reflect the dependence of the mold state.
본 발명의 (S) 유토머, 그의 (R) 대장체 및 참조로서 몰핀이 시험에 사용되었다. 수컷 마우스에서, 증가하는 양으로 생성물의 반복되는 양이 피하 경로에 의해 동물 체중의 0.20 ㎖/20 g의 양으로 2일 동안 투여된다. 1일차 10, 11, 12, 14 및 16시간 및 2일차 10, 12 및 14시간에 날옥손 용액을 복막내 경로로 100 ㎎/㎏의 양을 투여하고, 즉시 마우스당 경련의 횟수를 15분 동안 계수한다. 마우스의 배치당 경련의 평균 횟수 및 의존성 동물의 배치당 %가 계산된다. 결과를 하기 표에 나타낸다.(S) utomers of the invention, (R) colon and morphine as reference were used in the test. In male mice, repeated amounts of product in increasing amounts are administered for 2 days in an amount of 0.20 ml / 20 g of animal body weight by the subcutaneous route. At day 10, 11, 12, 14 and 16 hours and day 2, 10, 12 and 14 hours, the naloxone solution was administered in an intraperitoneal route at an amount of 100 mg / kg, and immediately the number of convulsions per mouse for 15 minutes. Count. The average number of convulsions per batch of mice and% per batch of dependent animals are calculated. The results are shown in the table below.
NT : 시험되지 않음NT: not tested
결과는 (S) 에난티오머가 피하 경로에 의해 투여된후 어떠한 중독 현상도 야기하지 않은 반면, 그의 (R) 대장체는 시험에서 양성 참조로서 사용된 몰핀으로 관찰된 정도를 도달하지 않고 이러한 상태를 야기한다.The results showed that (S) enantiomer did not cause any poisoning phenomenon after administration by the subcutaneous route, whereas its (R) colon did not reach the extent observed with the morphine used as a positive reference in the test, causing this condition. do.
d) - 생약 부분d)-herbal part
본 발명에 따른 약제학적 투약 형태의 예시를 위하여, 활성 성분로서 (S) 2-메틸아미노-2-페닐-n-부틸 3,4,5-트리메톡시벤조에이트 L(+) 타르트레이트(실시예 3의 생성물)을 포함하는 정제의 조성물 및 제제가 기술되어 있다.For illustration of the pharmaceutical dosage form according to the invention, as active ingredient (S) 2-methylamino-2-phenyl-n-butyl 3,4,5-trimethoxybenzoate L (+) tartrate Compositions and formulations of the tablets) are described.
실시예 3의 생성물 1 내지 75 ㎎1-75 mg of product of Example 3
락토오스 124 내지 74 ㎎Lactose 124-74 mg
미세결정 셀룰로오스 36 내지 60 ㎎36-60 mg microcrystalline cellulose
폴리비닐피롤리돈 6 ㎎Polyvinylpyrrolidone 6 mg
나트륨 카르복시메틸스타치 8 ㎎Sodium carboxymethyl starch 8 mg
스테아르산 마그네슘 1 ㎎1 mg magnesium stearate
활성 성분, 락토오스, 미세결정 셀룰로오스 및 카르복시메틸스타치를 혼합한다. 적절한 농도의 폴리비닐피롤리돈의 알콜 용액의 보조로 침윤시키고 과립화한다. 건조시키고 과립의 치수로 제조한다. 스테아르산 마그네슘과 균일하게 혼합한후, 정제당 200 ㎎으로 정제화한다.The active ingredient, lactose, microcrystalline cellulose and carboxymethylstarch are mixed. Infiltrate with the alcohol solution of polyvinylpyrrolidone at the appropriate concentration and granulate. Dried and prepared to the dimensions of the granules. After homogeneous mixing with magnesium stearate, it is tableted to 200 mg per tablet.
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| FR9708323A FR2765218B1 (en) | 1997-06-30 | 1997-06-30 | 2 (METHYLAMINO-2-PHENYL-N- BUTYL) 3,4,5-TRIMETHOXYBENZOATE (S), ITS APPLICATION TO THE TREATMENT OF CHRONIC PAIN |
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-
1997
- 1997-06-30 FR FR9708323A patent/FR2765218B1/en not_active Expired - Fee Related
-
1998
- 1998-06-23 BR BR9810387-3A patent/BR9810387A/en not_active IP Right Cessation
- 1998-06-23 HU HU0003023A patent/HUP0003023A3/en unknown
- 1998-06-23 JP JP50625999A patent/JP2002508776A/en active Pending
- 1998-06-23 CA CA002285479A patent/CA2285479A1/en not_active Abandoned
- 1998-06-23 AU AU85405/98A patent/AU731887B2/en not_active Ceased
- 1998-06-23 MX MXPA99009120A patent/MXPA99009120A/en unknown
- 1998-06-23 WO PCT/EP1998/003825 patent/WO1999001417A1/en not_active Application Discontinuation
- 1998-06-23 IL IL13339898A patent/IL133398A0/en unknown
- 1998-06-23 PL PL98337665A patent/PL337665A1/en unknown
- 1998-06-23 EP EP98936382A patent/EP0993436A1/en not_active Withdrawn
- 1998-06-23 NZ NZ500212A patent/NZ500212A/en unknown
- 1998-06-23 KR KR1019997012424A patent/KR20010014294A/en not_active Application Discontinuation
- 1998-06-29 ZA ZA985668A patent/ZA985668B/en unknown
-
1999
- 1999-12-27 NO NO996496A patent/NO996496L/en not_active Application Discontinuation
- 1999-12-28 IS IS5324A patent/IS5324A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| AU8540598A (en) | 1999-01-25 |
| IS5324A (en) | 1999-12-28 |
| BR9810387A (en) | 2000-09-05 |
| FR2765218A1 (en) | 1998-12-31 |
| NO996496D0 (en) | 1999-12-27 |
| NO996496L (en) | 1999-12-27 |
| FR2765218B1 (en) | 1999-08-13 |
| IL133398A0 (en) | 2001-04-30 |
| MXPA99009120A (en) | 2005-01-10 |
| PL337665A1 (en) | 2000-08-28 |
| HUP0003023A3 (en) | 2001-12-28 |
| NZ500212A (en) | 2001-07-27 |
| HUP0003023A2 (en) | 2001-01-29 |
| AU731887B2 (en) | 2001-04-05 |
| JP2002508776A (en) | 2002-03-19 |
| CA2285479A1 (en) | 1999-01-14 |
| WO1999001417A1 (en) | 1999-01-14 |
| ZA985668B (en) | 1999-01-25 |
| EP0993436A1 (en) | 2000-04-19 |
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